The broad, long-term objective of the project is to understand the molecular basis for neurodegeneration in polyglutamine (polyQ) expansion disorders. The polyQ-expansion disorders belong to the family of autosomal-dominant and lethal neurodegenerative diseases that share a common molecular trigger (CAG repeat expansion). A number of toxic functions have been assigned to the polyQ-expanded proteins, but so far clear understanding of pathogenic mechanisms involved in these disorders is lacking. None of the polyQ- expansion disorders have a cure. Huntington's disease (HD) is the most extensively studied among polyQ- expansion disorders. Striatal medium spiny neurons (MSN) are selectively affected in HD. PolyQ-expansion in Huntingtin protein (Httexp) is a molecular cause of HD. My laboratory recently discovered that Httexp directly binds to and activates the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), an intracellular Ca2+ release channel. Furthermore, we demonstrated a direct connection between abnormal neuronal Ca2+ signaling and apoptosis of HD MSN in in vitro experiments. Now I propose to further test Ca2+ hypothesis of HD. I also propose to apply similar ideas to understanding the mechanisms of pathogenesis in spinocerebellar ataxia type 3 (SCA3), another member of polyQ-expansion disorders family. Specifically, I propose: 1. To analyze biochemical and functional interactions between InsP3R1 and polyQ-expanded Huntingtin protein. To test Ca2+ hypothesis of HD in experiments with HD-YAC128 mouse model of HD. 2. To analyze biochemical and functional interactions between InsP3R1 and polyQ-expanded ataxin-3 protein. To test Ca2+ hypothesis of SCA3 in experiments with SCA3-YAC84Q mouse model of SCA3. 3. To validate our results in Ca2+ imaging and biochemical experiments with primary fibroblasts from human HD and SCA3 patients Our experiments will provide a critical test for a role of deranged Ca2+ signaling in pathogenesis of HD and SCA3 and may have implications for understanding and treatment of other polyQ-expansion disorders. The proposed project will have direct and immediate relevance for public health. Huntington's disease (HD) and Spinocerebellar Ataxia type 3 (SCA3) are incurable genetic disorders that cause enormous suffering. The experiments described in the grant are aimed at testing specific hypothesis regarding pathogenesis of these diseases and will provide information critical for development of the cure.